(S)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one | 1523412-59-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: (S)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
• 英文别名: (2S)-8-[(3R)-3-methylmorpholin-4-yl]-2-(trifluoromethyl)-1,2,3,4-tetrahydropyrimido[1,2-a]pyrimidin-6-one；(S)-8-((R)-3-methylmorpholino)-2-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one；(8S)-2-[(3R)-3-methylmorpholin-4-yl]-8-(trifluoromethyl)-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
• CAS: 1523412-59-0
• 化学式: C₁₃H₁₇F₃N₄O₂
• 分子量: 318.299
• InChiKey: KJCMHWUVQPPPCG-BDAKNGLRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.21
• 重原子数：
  22.0
• 可旋转键数：
  1.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  59.39
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (S)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one 在 sodium tetrahydroborate 、 caesium carbonate 作用下， 以 乙腈 为溶剂， 生成 (2S)-1-(2-hydroxy-3-methylbutyl)-8-((R)-3-methylmorpholino)-2-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one
  参考文献：
  名称：

  [EN] NOVEL 2,3-DIHYDRO-1H-IMIDAZO{1,2-a}PYRIMIDIN-5-ONE and this1,2,3,4-TETRAHYDROPYRIMIDO{1,2-a}PYRIMIDIN-6-ONE DERIVATIVES COMPRISING A SUBSTITUTED MORPHOLINE, PREPARATION THEREOF AND PHARMACEUTICAL USE THEREOF
  [FR] NOUVEAUX DÉRIVÉS DE 2,3-DIHYDRO-1H-IMIDAZO{1,2-A}PYRIMIDIN-5-ONE ET DE 1,2,3,4-TÉTRAHYDROPYRIMIDO{1,2-A}PYRIMIDIN-6-ONE COMPRENANT UNE MORPHOLINE SUBSTITUÉE, LEUR PROCÉDÉ DE PRÉPARATION ET LEUR UTILISATION PHARMACEUTIQUE

  摘要：

  公开号：

  WO2013190510A3
• 作为产物：
  描述：

  2-hydroxy-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 在 三乙胺 、 三氯氧磷 作用下， 以 乙醇 、 正庚烷 、 1,2-二氯乙烷 为溶剂， 反应 4.5h， 生成 (S)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
  参考文献：
  名称：

  Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors

  摘要：

  Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.

  DOI：

  10.1021/jm5013352

文献信息

• [EN] NOVEL 2,3-DIHYDRO-1H-IMIDAZO{1,2-a}PYRIMIDIN-5-ONE and this1,2,3,4-TETRAHYDROPYRIMIDO{1,2-a}PYRIMIDIN-6-ONE DERIVATIVES COMPRISING A SUBSTITUTED MORPHOLINE, PREPARATION THEREOF AND PHARMACEUTICAL USE THEREOF<br/>[FR] NOUVEAUX DÉRIVÉS DE 2,3-DIHYDRO-1H-IMIDAZO{1,2-A}PYRIMIDIN-5-ONE ET DE 1,2,3,4-TÉTRAHYDROPYRIMIDO{1,2-A}PYRIMIDIN-6-ONE COMPRENANT UNE MORPHOLINE SUBSTITUÉE, LEUR PROCÉDÉ DE PRÉPARATION ET LEUR UTILISATION PHARMACEUTIQUE
  申请人：SANOFI SA

  公开号：WO2013190510A3

  公开（公告）日：2014-03-06
• Discovery of (2<i>S</i>)-8-[(3<i>R</i>)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2<i>H</i>-pyrimido[1,2-<i>a</i>]pyrimidin-6-one: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors
  作者：Benoit Pasquier、Youssef El-Ahmad、Bruno Filoche-Rommé、Christine Dureuil、Florence Fassy、Pierre-Yves Abecassis、Magali Mathieu、Thomas Bertrand、Tsiala Benard、Cédric Barrière、Samira El Batti、Jean-Philippe Letallec、Véronique Sonnefraud、Maurice Brollo、Laurence Delbarre、Véronique Loyau、Fabienne Pilorge、Luc Bertin、Patrick Richepin、Jérôme Arigon、Jean-Robert Labrosse、Jacques Clément、Florence Durand、Romain Combet、Pierre Perraut、Vincent Leroy、Frédéric Gay、Dominique Lefrançois、François Bretin、Jean-Pierre Marquette、Nadine Michot、Anne Caron、Christelle Castell、Laurent Schio、Gary McCort、Hélène Goulaouic、Carlos Garcia-Echeverria、Baptiste Ronan

  DOI：10.1021/jm5013352

  日期：2015.1.8

  Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.